AVANZANDO EN LA APLICACIÓN DE BIOPSIA LÍQUIDA EN CÁNCER DE VEJIGA -
IMPROVING THE APPLICATION OF LIQUID BIOPSY FOR BLADDER CANCER
Urbano Anido Herranz Department of Medical Oncology | University Clinical Hospital of
Santiago de Compostela (CHUS) Traslational Medical Oncology (ONCOMET) | Health Research
Institute (IDIS) E-mail: [email protected]
Twitter: @urbano_anido
DISCLOSURE
1 CONSULTANT OR ADVISORY BOARD
2 GRANT OR TRAVEL SUPPORT
3 HONORARIA
4 PARTICIPATION IN CLINICAL TRIALS
Pfizer, Novartis, Bayer, Ipsen, EUSA, Sanofi, AAA
BMS, Pfizer, Novartis, Bayer, Ipsen, Sanofi, Pierre Fabre, Roche, Astellas, Rovi
BMS, Bayer, Ipsen, Novartis, Janssen, Astellas, AAA, Kyowa Kirin, Lilly, Pfizer, EUSA, Eisai, Merck
Pfizer, Astra Zeneca, MSD, Astellas, Janssen, Ipsen, Clovis, Roche, Bayer, BMS
NMIBC(CVSIM) (Tis, Ta, T1) ≈51-75% 1-4
MIBC (T2, T3a, T3b)
≈30-42% 1,4
Metastatic disease (T4)
≈4% 1,5
Uréteres
Uretra
1. Howlader N, et al. (eds). SEER Cancer Statistics Review 1975–2013; 2. NCCN Guidelines – Bladder Cancer v1.2017; 3. Sharma S, et al. Am Fam Physician 2009;80:717-23. 4. Kaufman DS, et al. Lancet 2009;374:239-49.
Staging and diagnosis
Survival
73.0% 78.1% 78.0%
1975–1977 1985–1989 2009
5-years survival at diagnosis1
1. SEER Stat Fact Sheets
50% of patients treated with radical intention will develop metastases and die by urothelial carcinoma
Mutational heterogeneity in cancer
Lawrence MS, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-8
DNA repair alterations
Mouw WK. DNA Repair Pathway Alterations in Bladder Cancer. Cancers (Basel). 2017;9(4).
BRCA1 and ERCC1 in BC
Font A, Taron M, Gago JL, Costa C, Sánchez JJ, Carrato C, et al. BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer. Annals of Oncology. 2011 Jan;22(1):139–44. Bellmunt J, Paz-Ares L, Cuello M, Cecere F, Albiol S, Guillem V, et al. Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy. Ann Oncol. 2006 Nov 2;18(3):522–8.
BRCA1 ERCC1
Somatic ERCC2 Mutations
Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, et al. Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma.
Cancer Discovery. 2014 Sep 30;4(10):1140–53.
ERCC2 & neoadyuvant chemotherapy
JAMA Oncol. 2016;2(8):1094-1096. doi:10.1001/jamaoncol.2016.1056
Genomic characterization
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014 Mar 20;507(7492):315–22.
Genomic characterization
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014 Mar 20;507(7492):315–22.
Molecular classification of urothelial carcinoma: global mRNA classification versus tumour‐cell phenotype classification
The Journal of Pathology, Volume: 242, Issue: 1, Pages: 113-125, First published: 13 February 2017, DOI: (10.1002/path.4886)
Luminal KRT20+, GATA3+, FOXA1+
Basal/Escamoso KRT5,6,14+, GATA3-, FOXA1-
Luminal-Papilar Luminal-Infiltrado Luminal Basal/Escamoso Neuronal
FGFR mut, fus, amp Histología papilar SHH+ CIS bajo
Bajo riesgo NAC* FGFR3 inhibidores
Baja pureza Marcadores TEM miRNA-200 PD-L1, CTLA-4 medio Marcadores miofibroblasto p53 like
Anti-PD-1/PD-L1/ CTLA-4
NAC cisplatino**
UPKs KRT20 sNX31
Terapias diana
Mujeres Diferenciación escamosa Marcadores basales de keratinas PD-L1 y CTLA-4 altos Infiltrado inmune
Anti-PD-1/PD-L1/ CTLA-4
NAC cisplatino
SOX2 DLX6 MSI1 PLEKHG4B E2F3/SOX4 amp Ciclo celular alto
Etopósido-cisplatino y NAC
*Baja probabilidad de respuesta
**Baja tasa de respuesta
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. Nature Publishing Group; 2014 Mar 20;507(7492):315–22.
Protocol
unpublished
SOGPLA 2016-01. Estudio prospectivo de la utilidad de la biopsia líquida como factor predictor y pronóstico en pacientes con carcinoma urotelial metastásico en progresión tras quimioterapia basada en platino
95 prospectively collected samples
Baseline samples
n=48
3 cycles of therapy samples
n=24
Progression samples
n=17
51 metastatic bladder cancer patients from
18/24 spanish hositals
Patients with Baseline samples +
3 cycles therapy samples
n=16
Patients with Baseline +
3 cycles therapy + Progression
samples n=9
Patients with Baseline samples +
Progression samples
n=9
Patients with Only Baseline
samples
n=9
CTCs was studied in 89 samples from 51 patients
(6 samples were excluded due to technical problems)
unpublished
SOGPLA 2016-01. Estudio prospectivo de la utilidad de la biopsia líquida como factor predictor y pronóstico en pacientes con carcinoma urotelial metastásico en progresión tras quimioterapia basada en platino
Recruitment
unpublished
SOGPLA 2016-01. Estudio prospectivo de la utilidad de la biopsia líquida como factor predictor y pronóstico en pacientes con carcinoma urotelial metastásico en progresión tras quimioterapia basada en platino
Number of CTCs
There are 52 patients of 18/24 spanish hospitals, and in 23 (44.23%) patients there was no basal CTCs. There were 55.75% of CTC detection. In patients with no basal CTCs (23), only 6 presented lastly CTCs (on progresión) (2, 3, 19, 2, 2 y 1). In 5 patients at the begining Veridex cancels sample in CellSearch because of low volumen.
unpublished
SOGPLA 2016-01. Estudio prospectivo de la utilidad de la biopsia líquida como factor predictor y pronóstico en pacientes con carcinoma urotelial metastásico en progresión tras quimioterapia basada en platino
Median of CTCs by cycle
unpublished
SOGPLA 2016-01. Estudio prospectivo de la utilidad de la biopsia líquida como factor predictor y pronóstico en pacientes con carcinoma urotelial metastásico en progresión tras quimioterapia basada en platino
Changes in CTCs by cycle and progression
unpublished
SOGPLA 2016-01. Estudio prospectivo de la utilidad de la biopsia líquida como factor predictor y pronóstico en pacientes con carcinoma urotelial metastásico en progresión tras quimioterapia basada en platino
Overall survival
Median 10.05 months (CI95% 7.98 – 14.78)
12-months survival 47.5% (CI95% 34.14 – 66.1)
24-months survival 6.17% (CI95% 1.12 – 33.9)
unpublished
SOGPLA 2016-01. Estudio prospectivo de la utilidad de la biopsia líquida como factor predictor y pronóstico en pacientes con carcinoma urotelial metastásico en progresión tras quimioterapia basada en platino
By initial number of CTCs
unpublished
SOGPLA 2016-01. Estudio prospectivo de la utilidad de la biopsia líquida como factor predictor y pronóstico en pacientes con carcinoma urotelial metastásico en progresión tras quimioterapia basada en platino
By change in CTCs
unpublished
SOGPLA 2016-01. Estudio prospectivo de la utilidad de la biopsia líquida como factor predictor y pronóstico en pacientes con carcinoma urotelial metastásico en progresión tras quimioterapia basada en platino
ctDNA in BC
Birkenkamp-Demtroder K, Christensen E, Nordentoft I, Knudsen M, Taber A, Hoyer S, et al. Monitoring Treatment Response and Metastatic Relapse in Advanced Bladder Cancer by Liquid Biopsy Analysis. Eur Urol. 2018;73(4):535-40.
Monitoring ctDNA
Christensen E, Nordentoft I, Vang S, Birkenkamp-Demtroder K, Jensen JB, Agerbaek M, et al. Optimized targeted sequencing of cell-free plasma DNA from bladder cancer patients. Sci Rep. 2018;8(1):1917.
Monitoring ctDNA
Christensen E, Birkenkamp-Demtroder K, Sethi H, Shchegrova S, Salari R, Nordentoft I, et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J Clin Oncol. 2019;37(18):1547-57.
Monitoring ctDNA
Christensen E, Birkenkamp-Demtroder K, Sethi H, Shchegrova S, Salari R, Nordentoft I, et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J Clin Oncol. 2019;37(18):1547-57.
Conclusions
• Liquid biopsy, including blood & urine, have several potential applications in BC and could lead to optimized management, early diagnosis and better survival.
• The high somatic mutation rate in BC indicates this cancer is ideally suited for ctDNA both in blood and in urine.
• Preliminary studies have showed ctDNA has a potential role as:
• A marker of aggressiveness in localised disease
• An indicator of early recurrence after radical treatment
• A prognostic biomarker of reduced survival
• Monitorization of treatment response
• The emergence in the clinic of approved molecularly-targeted drugs based on identifiable genomic biomarkers helps to develop the possibility to transfer the use of liquid biopsy from bench to bedside in BC.
• Larger prospective studies, better methods of isolation and knowledge of BC biology are needed.
MUCHAS GRACIAS THANK YOU
Urbano Anido Herranz
Department of Medical Oncology | University Clinical Hospital of Santiago de Compostela (CHUS)
Traslational Medical Oncology (ONCOMET) | Health Research Institute (IDIS)
E-mail: [email protected]
Twitter: @urbano_anido